Doi:10.1016/j.eururo.2006.03.018

e u r o p e a n u r o l o g y 5 0 ( 2 0 0 6 ) 2 1 5 – 2 1 7 a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m Editorial – referring to the article published on pp. 351–359 of this issue Treatment of Erectile Dysfunction with Chronic Dosingof Tadalafil The medical management of erectile dysfunction significant cardiac risk factors, suggesting that ED (ED) was re-defined following the recognition that may be the first clinical manifestation of cardiovas- the signalling system of nitric oxide–cyclic guano- sine-3050-monophosphate (NO-cGMP) was pivotal in It is speculative—but likely—that chronic PDE-5 the production of the arterial dilation and venous inhibitor treatment will improve endothelial func- occlusion necessary to attain and sustain an erec- tion and cardiovascular health in general. Sildenafil tion. In parallel with this new understanding of the has been reported to improve endothelium-depen- mechanism of penile erection, several phospho- dent, flow-mediated vasodilatation in smokers and diesterase type 5 inhibitor drugs (PDE-5s), which in patients with diabetes mellitus or chronic heart inhibit the breakdown of cGMP producing vasodila- failure . Chronic therapy with tadalafil has been tation and improve endothelial cell function, have reported to improve endothelial function and been developed and demonstrated to be effective in erectile function in patients with and without treating erectile dysfunction. However, the para- cardiovascular risk factors Chronic treatment digm for the medical treatment of erectile dysfunc- with a PDE-5 inhibitor may produce functional tion remains unchanged in that it includes on- tissue modifications involving upregulation of demand dosing of medication. Whilst on-demand either muscarinic receptors or the transduction dosing reflects the intermittent nature of sexual mechanisms leading to the activation of endothelial intercourse, currently is more cost-effective than nitric oxide synthase . In addition to their role in chronic dosing and may be reasonable for many the treatment of erectile dysfunction and pulmon- men with erectile dysfunction, it ignores the ary hypertension, recent reports suggest a potential potential corporal, cardiovascular and relationship role exists for the use of daily PDE-5 inhibitors in the benefits of chronic PDE-5 inhibitor dosing.
treatment of other forms of cardiovascular disease Penile vascular disease is the most common such as hypertension. Although administration of cause of erectile dysfunction, accounting for up to PDE-5 inhibitors to healthy normotensive subjects 80% of cases. Abnormalities of the NO-cGMP– results in only modest lowering of systolic and signalling system attributable to endothelial dys- diastolic arterial pressures, a greater decrease may function are present in atherosclerosis and play an occur in subjects with hypertension and increased important role in the pathophysiology of erectile systemic vasoconstriction related to raised levels of dysfunction . Endothelial dysfunction may be angiotensin II, especially if angiotensin II antago- present in patients with ED even in the absence of DOI of original article: 10.1016/j.eururo.2006.02.052* Tel. +61 2 94373906; Fax: +61 2 99065900.
E-mail address: 0302-2838/$ – see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. e u r o p e a n u r o l o g y 5 0 ( 2 0 0 6 ) 2 1 5 – 2 1 7 The prolonged half-life of tadalafil (17.5 hours) pared with on-demand tadalafil ( p < 0.05). At the and the resultant prolonged 36-hour period of completion of the study, 72% preferred daily responsiveness constitute an ideal pharmacokinetic tadalafil. The 14 European country, multicenter, profile for chronic dosing, compared with short half- crossover, open-label SURE study examined subject life PDE-5 inhibitor drugs. Over a dose range of 2.5 to preference for tadalafil taken on-demand or 3 times/ 20 mg, tadalafil systemic exposure increases pro- week The authors reported that both regimens portionally with the dose in healthy subjects.
were efficacious and well tolerated, and that 42.2% Steady-state plasma concentrations are attained of subjects preferred the 3 times/week treatment.
within 5 days of once-daily dosing, and exposure is However, differences in study design, duration of approximately 1.6-fold greater than after a single treatment, dosing regimens, study population demography, eligibility criteria, study outcome In the first randomised placebo controlled trial of measures and methods of data analysis make daily dosing of tadalafil, Porst et al. report that comparison between studies difficult. Furthermore, once-daily dosing of tadalafil 5 and 10 mg signifi- preference studies have inherent methodologic cantly improved all erectile function primary and flaws, resulting in poor internal validity attributable secondary outcome measures, compared with pla- to study design biases and confounding errors, thus cebo ( p < 0.001), and was well tolerated. Successful making generalization of their results to men completion of intercourse was reported in 72.8% of seeking treatment for ED difficult or impossible.
attempts with tadalafil 10 mg, compared with 36.7% Whilst chronic dosing of tadalafil may have a with placebo. Furthermore, the EF domain score was potential role as a treatment for ED, its utility is increased into the normal range (26) in 50.5% of limited by current high cost and the reality that the subjects treated with tadalafil 10 mg. Of particular average 5–6 times per month intercourse require- interest is the report that changes from baseline to ments of the typical ED patient are met adequately end point were similar for both doses of tadalafil, by on-demand tadalafil. Tablet splitting, although suggesting 5 mg as the optimal starting dose. The not recommended by the manufacturer, is common frequency of treatment emergent adverse events in daily office practice and may reduce the cost of was similar to that reported in an earlier integrated chronic dosing to a level acceptable to many analysis of 11 on-demand tadalafil trials and patients. A potential role exists for chronic dosing included dyspepsia, headache, dyspepsia, back pain of tadalafil, alone or in combination with on- and myalgia. These adverse effects were mild to demand tadalafil or intracavernous injection ther- moderate in severity in 86.6% of subjects, prompted apy, in the salvage of on-demand PDE-5 failure in discontinuation of the study in 3.4% of subjects and patients with severe and challenging ED such as reflect the pharmacologic action of tadalafil as a diabetic ED, severe vasculogenic ED, post-radical prostatectomy ED or comorbid hypertension. Of Efficacy, tolerability and preference for chronic particular interest is the putative place of chronic dosing of tadalafil have been reported previously by dosing of tadalafil for ED prophylaxis in men other authors using once-daily or alternate following a nerve-sparing radical retropubic pros- day dosing regimens in uncontrolled, open-label tatectomy (NSRRP) in which intraoperative neur- design studies. Daily dosing of tadalafil (10–20 mg) apraxia may delay recovery of cavernous nerve was reported as an effective salvage therapy for function and return of potency for up to 2 years. It is patients unresponsive to on-demand tadalafil widely accepted that early ED prophylaxis/treat- In a study population of men with severe, pre- ment may interrupt the progressive apoptotic loss of dominantly organic ED and a high incidence of corporal smooth muscle and the increased deposi- vascular risk factors who satisfied rigorous criteria tion of extracellular matrix attributable to chronic, for on-demand tadalafil treatment failure, daily corporal, hypoxia-induced, increased production of dosing of tadalafil significantly enhanced all efficacy transforming growth factor-b1, which results in the outcome variables, compared with baseline and on- eventual development of structurally based corpor- eal veno-occlusive dysfunction. Levine et al. In a second study, the efficacy and safety of on- reported that nightly administration of sildenafil demand tadalafil 20 mg and daily tadalafil 10 mg post-NSRRP increased the return of spontaneous were compared by using a 26-week, open-label, erections 6-fold, compared with placebo.
parallel arm, crossover study design . The mean Randomised, open-label, comparator and patient change from baseline for all erectile function PDE-5 preference studies have highlighted the primary and secondary outcome measures was importance that patients place on the ability to significantly higher for daily-dosed tadalafil, com- achieve an erection several hours after dosing, as e u r o p e a n u r o l o g y 5 0 ( 2 0 0 6 ) 2 1 5 – 2 1 7 seen with long half-life PDE-5 inhibitors such as [3] Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JL, tadalafil, and report higher levels of overall patient Bank AJ. Impaired brachial artery endothelium-depen- satisfaction, compared with sildenafil With dent and -independent vasodilation in men with erectile regards to the reestablishment of sexual spontane- dysfunction and no other clinical cardiovascular disease. J ity as an important treatment attribute, some [4] Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA.
patients may chose chronic dosing regimens to Acute and prolonged effects of sildenafil on brachial almost completely remove the need for planning a artery flow-mediated dilatation in type 2 diabetes. Dia- sexual encounter. Furthermore, younger men with psychogenic ED often report on-demand PDE-5 [5] Kimura M, Higashi Y, Hara K, et al. PDE5 inhibitor silde- inhibitor failure on those occasions when they nafil citrate augments endothelium-dependent vasodila- needed to plan sexual activity; their concern that tion in smokers. Hypertension 2003;41:1106–10, Epub 2003 on-demand PDE-5 inhibitors may not be effective exacerbate already present high levels of perfor- [6] Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S.
mance anxiety. Interim tadalafil chronic-dosing Acute type 5 phosphodiesterase inhibition with sildenafil regimens alone or in combination with cognitive enhances flow-mediated vasodilation in patients with behavioural therapy potentially may offer these chronic heart failure. J Am Coll Cardiol 2000;36:845–51.
[7] Rosano GMC, Aversa A, Vitale C, Fabbri A, Fini M, Spera G.
patients a higher level of efficacy assurance and Chronic treatment with tadalafil improves endothelial improved treatment outcomes, and may improve function in men with increased cardiovascular risk. Eur the potential for restoration of potency.
In conclusion, treatment of ED with daily tadalafil [8] Caretta N, Palego P, Ferlin A, et al. Resumption of sponta- appears effective, safe and well tolerated. Chronic neous erections in selected patients affected by erectile dosing regimens of tadalafil may have a role in the dysfunction and various degrees of carotid wall altera- routine management of selected patients with ED, in tion: role of tadalafil. Eur Urol 2005;48:326–31.
the management of treatment refractory ED or as [9] Behr-Roussel D, Gorny D, Mevel K, et al. Chronic sildenafil post-NSRRP ED prophylaxis. It may be associated enhances erectile responses and endothelium-dependent with higher levels of patient and partner sexual, and corporal relaxations of normal rats: lack of tachyphylaxis.
overall satisfaction and consequential improve- ments in the quality of relationships. Further [10] Jackson G. Hemodynamic and exercise effects of phos- phodiesterase 5 inhibitors. Am J Cardiol 2005;96:32M–6M.
controlled efficacy, tolerability and patient prefer- [11] Porst H, Giuliano F, Glina S, et al. Evaluation of the efficacy ence studies are required to determine the optimal and safety of once-a-day dosing of tadalafil 5 mg and dose, the frequency of chronic dosing, the time 10 mg in the treatment of erectile dysfunction: results course for improvement in erectile function, the of a multicenter, randomized, double-blind, placebo- potential for the development of drug tolerance and controlled trial. Eur Urol 2006;50:351–9.
the full spectrum of patient and partner psycholo- [12] McMahon CG. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to on-demand tadalafil. J Sex Med 2004;1:292–300.
[13] McMahon CG. Comparison of efficacy, safety, and toler- ability of on-demand tadalafil and daily dosed tadalafil for Dr McMahon is an investigator, member of an advi- the treatment of erectile dysfunction. J Sex Med 2005;2:415–25.
sory board and/or speaker’s panel for Johnson & [14] Mirone V, Costa P, Damber JE, et al. An evaluation of an Johnson, Janssen-Cilag, Ortho McNeil, Pfizer, Icos- alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14European countries. Eur Urol 2005;47:846–54.
[15] Levine LA, McCullough AR, Padma-Nathan H. Longitudi- nal randomized placebo-controlled study of the return ofnocturnal erections after nerve-sparing radical prosta- [1] Azadzoi KM, Saenz de Tejada I. Hypercholesterolemia tectomy in men treated with nightly sildenafil citrate.
impairs endothelium-dependent relaxation of rabbit cor- pus cavernosum smooth muscle. J Urol 1991;146:238–40.
[16] Eardley I, Mirone V, Montorsi F, et al. An open-label, [2] Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen multicentre, randomized, crossover study comparing RA. Impaired neurogenic and endothelium-mediated sildenafil citrate and tadalafil for treating erectile dys- relaxation of penile smooth muscle from diabetic men function in men naive to phosphodiesterase 5 inhibitor with impotence. N Engl J Med 1989;320:1025–30.

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